Elsevier

Clinica Chimica Acta

Volume 458, 1 July 2016, Pages 23-29
Clinica Chimica Acta

Meaningful interpretation of serum HER2 ECD levels requires clear patient clinical background, and serves several functions in the efficient management of breast cancer patients

https://doi.org/10.1016/j.cca.2016.04.025Get rights and content

Highlights

  • Serum ECD and tissue HER2 levels are consistent in untreated tumor-bearing patients.

  • The prognostic value of serum ECD was demonstrated using cut-off of 15.0 ng/ml.

  • Patients with elevated ECD had shorter progression-free survival (PFS).

  • Elevated ECD was an adverse predictor for PFS in response to anti-HER2 therapy.

  •  20% decreased ECD was associated with longer PFS in the patients.

Abstract

Background

This study was initiated to evaluate the clinical significant of HER2 extracellular domain (ECD) in the real-time management of breast cancer patients.

Methods

Five-hundred forty-six eligible breast cancer patients were divided according to their clinical background. The correlation between ECD, tissue HER2, and clinical outcome of the patients were analyzed.

Results

Receiver operating characteristic analysis revealed that ECD measured before receiving neoadjuvant therapy yielded the highest area under the curve (0.9185; P < 0.0001), indicating that ECD and tissue HER2 levels are consistent in untreated tumor-bearing patients. At cut-off of 15.0 ng/ml, the prognostic value of ECD was demonstrated using univariate (HR = 1.664, P < 0.0001) and multivariate (HR = 1.547, P = 0.011) Cox regression analysis. Kaplan-Meier survival curves revealed that patients with elevated ECD had shorter progression-free survival (PFS) (4.0 vs. 6.1 months, P < 0.0001). Elevated ECD was also an adverse predictor for PFS in response to anti-HER2 therapy (4.3 vs. 10.2 months, P = 0.0155). In contrast, ≥ 20%, decreased ECD was associated with longer PFS in patients who received anti-HER2 therapy (10.9 vs. 2.4 months, P = 0.0164) and overall (10.7 vs. 2.8 months, P = 0.0034).

Conclusions

A patient's clinical history can help determine whether ECD could provide added value for breast cancer management.

Introduction

Breast cancer, which has the highest incidence rate and second highest mortality rate of female malignant tumors [1], represents a great health problem all over the world. It has now been widely accepted that breast cancer can be divided into different subtypes according to its expression of estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) and Ki67 [2]. Each subtype carries with it a distinct prognosis, and responds differently to various treatments. Therefore, accurate characterization of breast cancer with respect to these biomarkers is essential for making appropriate treatment decisions that have the greatest positive impact on patient care.

HER2, also known as Erb-B2, is located at 17q21 in the human genome. It encodes a 185 kDa transmembrane tyrosine kinase receptor that significantly influences a cancer cell's survival and proliferation [3], [4]. The integral HER2 protein consists of three functional domains: the extracellular domain (ECD), which can bind with other members of HER family; the transmembrane segment with lipophilic properties; and the intracellular domain, which has tyrosine kinase activity. HER2 over-expression or gene amplification is reported in approximately 20% of breast cancer patients, and is usually associated with worse outcomes. Patients who are HER2 + require anti-HER2 therapy (trastuzumab or lapatinib) to improve the odds and length of survival [5], [6], [7]. Traditionally, HER2 status has been determined using immunohistochemistry (IHC) or in situ hybridization (ISH) on tumor tissue following biopsy [8], [9]. However, due to factors such as heterogeneity in tumor tissue, subjectivity in results interpretation, and variations in assay protocol, false negative or positive results may inevitably arise using the IHC and ISH methods [10], [11]. Meanwhile, growing evidence in recent years has revealed that patients who lose HER2 expression during the therapy may not get continuing benefit from anti-HER2 therapy, emphasizing the importance and necessity of real-time HER2 detection [12], [13], [14], [15]. Such monitoring as this is hard to perform, however, because repeated tissue biopsy is painful and infeasible for most patients in routine clinical practice. Consequently, a minimally invasive approach that could monitor the dynamically changing HER2 and augment information supplied by tissue methods has become an urgent need for the treatment of breast cancer.

It has been reported that the 97–115 kDa HER2 ECD can be released into serum by proteolytic cleavage of the protein, or alternative splicing of the HER2 transcript [16.17]. Taking advantage of this, measurement of serum HER2 ECD presents a less-invasive and easier to perform method for repeated assessments. For this reason, detection of serum HER2 ECD has attracted great attention for its promising application in real-time HER2 determination, dynamic disease monitoring, and evaluation [16], [17]. Unfortunately, despite these appealing prospects, the actual utilization of serum HER2 ECD in routine management of patients is hampered by the lack of consistent findings [18], [19], [20], [21], [22]. Possible explanations may include the variability between assays, use of diverse cut-offs, the heterogeneity of breast cancers, the ambiguous treatment history of the enrolled patients, and so on [21], [22].

Section snippets

Study design

Early stage breast cancer patients who were going to receive neoadjuvant or adjuvant therapy, as well as advanced stage patients who were going to receive a new line salvage therapy were enrolled in the present study. Eligible patients were required to have an Eastern Cooperative Oncology Group (ECOG) performance status score of 0 to 3, and a complete pathology report describing the tumor's histological type, grade, size, nodal and hormonal (ER, PR, HER2) receptor status. Within 3 days before

Patient characteristics

As indicated by the flowchart (Fig. 1), 546 breast cancer patients were enrolled between February 2012 and February 2015. Patients were divided into three groups: 84 early stage patients before receiving neoadjuvant therapy (group 1); 80 early stage patients after surgery and before receiving adjuvant therapy (group 2); and 382 advanced stage patients before receiving a new line of salvage therapy (group 3). The patient characteristics of the three groups are listed in Supplemental Table 1,

Discussion

Despite its attractive prospects, applying serum HER2 ECD testing in routine clinical management of breast cancer patients has been greatly hampered by the lack of consistent findings [18], [19], [20], [21], [22]. To avoid potential limitations arising in previous studies due to protocol design, we used an FDA approved assay to differentiate between results based on specific patient cohorts. Based on our data, our recommendations for the appropriate application of HER2 ECD in clinical practice

Conclusions

Based on our results and previous reports, we conclude that it's infeasible to replace tissue HER2 testing with serum HER2 ECD testing, but the combined application of these assays may provide more information to determine the real HER2 status of a patient. The appropriate use of information derived from HER2 ECD testing might be best defined by the clinical background of the patient, such as subtype, stage and previous treatment, and this information should be seriously considered when using

Acknowledgment

We acknowledge Yaohua Huang for assistance with statistical analyses and H. Roma Levy (Siemens Healthcare Diagnostics) for editing support. This work was supported by Siemens Healthcare Diagnostics (Shanghai) Co., Ltd (No. SHD-HERP01), the National Natural Science Foundation of China (No. 81472477 and 81572597), the Beijing Natural Science Foundation (No. 7132155), the Capital Application Research with Clinical Feature (No. Z151100004015212), the Translational Medicine Foundation of Academy of

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